For the past six years, we have been engaged in a study of the association between aluminum accumulation in the brain and Alzheimer's disease (AD). Using scanning electron microscopy with x-ray spectrometry, we have demonstrated evidence of aluminum accumulation within the neurofibrillary tangle-bearing neurons of cases of AD and in the brains of cases of Guamanian amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD). This proposal seeks funds to continue these studies utilizing the unique capacity for highly precise and extremely sensitive trace elements analysis of the laser microprobe mass analyzer (LAMMA) instrument which has recently been installed in our laboratory. This newly developed instrument provides mass spectrometry analysis of sectioned plastic-embedded tissues using an optically directed, narrowly focused high energy laser beam. The LAMMA instrument combines a lateral resolution of 1 micron, elemental detection limits in the range of 1 part per million, and the ability to permit unequivocal identification of the cell being analyzed. Under the research being proposed, we will utilize LAMMA analysis to determine the distribution of aluminum and other trace elements within tangle-bearing and tangle-free neurons identified in the hippocampus, neucleus basalis of Meynert and frontal cortex of cases of AD, Guamanian ALS and PD and normal controls. Studies will be performed to determine the intraneuronal distribution of aluminum in cells showing granulovacuolar degeneration and the trace element constituents of senile plaques. Finally, we will investigate two other conditions in which aluminum accumulates within the nervous system, namely, dialysis encephalopathy and experimentally induced neurofilamentous changes seen in rabbits exposed intracisternally to aluminum salts. Because of the unique capabilities of laser microprobe technology, these studies will allow us to define, with greater precision than previously possible, the extent and nature of aluminum deposition in the brain with respect to the pathogenesis of neurofibrillary tangles and AD.